tbuckley/cabot-search huggingface dataset:
Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia/reperfusion in mice
Authors: Yi-Heng Wang, Zheng-Zheng Yan, Si-Dan Luo, Jing-Juan Hu, Mei Wu, Jin Zhao, Wei-Feng Liu, Cai Li, Ke-Xuan Liu
Journal: European Respiratory Journal (2022)

Introduction Acute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischaemia/reperfusion (I/R). The gut microbiota and its metabolic byproducts act as important modulators of the gut–lung axis. This study aimed to define the role of succinate, a key microbiota metabolite, in intestinal I/R-induced ALI progression. Methods Gut and lung microbiota of mice subjected to intestinal I/R were analysed using 16S rRNA gene sequencing. Succinate level alterations were measured in germ-free mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor 1 ( Sucnr1 )-deficient mice and in murine alveolar macrophages transfected with Sucnr1 -short interfering RNA. Succinate levels were measured in patients undergoing cardiopulmonary bypass, including intestinal I/R. Results Succinate accumulated in lungs after intestinal I/R, and this was associated with an imbalance of succinate-producing and succinate-consuming bacteria in the gut, but not the lungs. Succinate accumulation was absent in germ-free mice and was reversed by gut microbiota depletion with antibiotics, indicating that the gut microbiota is a source of lung succinate. Moreover, succinate promoted alveolar macrophage polarisation, alveolar epithelial apoptosis and lung injury during intestinal I/R. Conversely, knockdown of Sucnr1 or blockage of SUCNR1 in vitro and in vivo reversed the effects of succinate by modulating the phosphoinositide 3-kinase-AKT/hypoxia-inducible factor-1α pathway. Plasma succinate levels significantly correlated with intestinal I/R-related lung injury after cardiopulmonary bypass. Conclusion Gut microbiota-derived succinate exacerbates intestinal I/R-induced ALI through SUCNR1-dependent alveolar macrophage polarisation, identifying succinate as a novel target for gut-derived ALI in critically ill patients.
A Conductive Bioengineered Cardiac Patch for Myocardial Infarction Treatment by Improving Tissue Electrical Integrity
Authors: Qi Yin, Ping Zhu, Wei Liu, Zhongbao Gao, Luming Zhao, Chunlan Wang, Siwei Li, Miaomiao Zhu, Qi Zhang, Xiao Zhang, Changyong Wang, Jin Zhou
Journal: Advanced Healthcare Materials (2022)

Abstract Conductive scaffolds are of great value for constructing functional myocardial tissues and promoting tissue reconstruction in the treatment of myocardial infarction (MI). Here, a novel scaffold composed of silk fibroin and polypyrrole (SP50) with a typical sponge‐like porous structure and electrical conductivity similar to the native myocardium is developed. An electroactive engineered cardiac patch (SP50 ECP) with a certain thickness is constructed by applying electrical stimulation (ES) to the cardiomyocytes (CMs) on the scaffold. SP50 ECP can significantly express cardiac marker protein ( α ‐actinin, Cx‐43, and cTnT) and has better contractility and electrical coupling performance. Following in vivo transplantation, SP50 ECP shows a notable therapeutic effect in repairing infarcted myocardium. Not only can SP50 ECP effectively improves left ventricular remodeling and restore cardiac functions, such as ejection function (EF), but more importantly, improves the propagation of electrical pulses and promote the synchronous contraction of CMs in the scar area with normal myocardium, effectively reducing the susceptibility of MI rats to arrhythmias. In conclusion, this study demonstrates a facile approach to constructing electroactive ECPs based on porous conductive scaffolds and proves the therapeutic effects of ECPs in repairing the infarcted heart, which may represent a promising strategy for MI treatment.
Bronchial gene expression alterations associated with radiological bronchiectasis
Authors: Ke Xu, Alejandro A. Diaz, Fenghai Duan, Minyi Lee, Xiaohui Xiao, Hanqiao Liu, Gang Liu, Michael H. Cho, Adam C. Gower, Yuriy O. Alekseyev, Avrum Spira, Denise R. Aberle, George R. Washko, Ehab Billatos, Marc E. Lenburg
Journal: European Respiratory Journal (2022)

Objectives Discovering airway gene expression alterations associated with radiological bronchiectasis may improve the understanding of the pathobiology of early-stage bronchiectasis. Methods Presence of radiological bronchiectasis in 173 individuals without a clinical diagnosis of bronchiectasis was evaluated. Bronchial brushings from these individuals were transcriptomically profiled and analysed. Single-cell deconvolution was performed to estimate changes in cellular landscape that may be associated with early disease progression. Results 20 participants have widespread radiological bronchiectasis (three or more lobes). Transcriptomic analysis reflects biological processes associated with bronchiectasis including decreased expression of genes involved in cell adhesion and increased expression of genes involved in inflammatory pathways (655 genes, false discovery rate &lt;0.1, log 2 fold-change &gt;0.25). Deconvolution analysis suggests that radiological bronchiectasis is associated with an increased proportion of ciliated and deuterosomal cells, and a decreased proportion of basal cells. Gene expression patterns separated participants into three clusters: normal, intermediate and bronchiectatic. The bronchiectatic cluster was enriched by participants with more lobes of radiological bronchiectasis (p&lt;0.0001), more symptoms (p=0.002), higher SERPINA1 mutation rates (p=0.03) and higher computed tomography derived bronchiectasis scores (p&lt;0.0001). Conclusions Genes involved in cell adhesion, Wnt signalling, ciliogenesis and interferon-γ pathways had altered expression in the bronchus of participants with widespread radiological bronchiectasis, possibly associated with decreased basal and increased ciliated cells. This gene expression pattern is not only highly enriched among individuals with radiological bronchiectasis, but also associated with airway-related symptoms in those without discernible radiological bronchiectasis, suggesting that it reflects a bronchiectasis-associated, but non-bronchiectasis-specific lung pathophysiological process.
Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection
Authors: Alexander J. Mentzer, Daniel O’Connor, Sagida Bibi, Irina Chelysheva, Elizabeth A. Clutterbuck, Tesfaye Demissie, Tanya Dinesh, Nick J. Edwards, Sally Felle, Shuo Feng, Amy L. Flaxman, Eleanor Karp-Tatham, Grace Li, Xinxue Liu, Natalie Marchevsky, Leila Godfrey, Rebecca Makinson, Maireid B. Bull, Jamie Fowler, Bana Alamad, Tomas Malinauskas, Amanda Y. Chong, Katherine Sanders, Robert H. Shaw, Merryn Voysey, Ana Cavey, Angela Minassian, Arabella Stuart, Baktash Khozoee, Brama Hanumunthadu, Brian Angus, Catherine C. Smith, Iain Turnbull, Jonathan Kwok, Katherine R. W. Emary, Liliana Cifuentes, Maheshi N. Ramasamy, Paola Cicconi, Adam Finn, Alastair C. McGregor, Andrea M. Collins, Andrew Smith, Anna L. Goodman, Christopher A. Green, Christopher J. A. Duncan, Christopher J. A. Williams, Daniela M. Ferreira, David P. J. Turner, Emma C. Thomson, Helen Hill, Katrina Pollock, Mark Toshner, Patrick J. Lillie, Paul Heath, Rajeka Lazarus, Rebecca K. Sutherland, Ruth O. Payne, Saul N. Faust, Tom Darton, Vincenzo Libri, Rachel Anslow, Samuel Provtsgaard-Morys, Thomas Hart, Amy Beveridge, Syed Adlou, Matthew D. Snape, Andrew J. Pollard, Teresa Lambe, Julian C. Knight
Journal: Nature Medicine (2022)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we found that inter-individual variation in normalized antibody responses against SARS-CoV-2 spike and its receptor-binding domain (RBD) at 28 days after first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 ( P = 3.2 × 10 −9 ), which we replicated in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha variant waves compared to non-carriers (hazard ratio = 0.63, 0.42–0.93, P = 0.02). We identified a distinct spike-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared to other similar alleles, and we found evidence of increased spike-specific memory B cell responses in HLA-DQB1*06 carriers at 84 days after first vaccination. Our results demonstrate association of HLA type with Coronavirus Disease 2019 (COVID-19) vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.
JAK/BCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL
Authors: Aissa Benyoucef, Katharina Haigh, Andrew Cuddihy, Jody J. Haigh
Journal: Leukemia (2022)

Abstract ETP-ALL (Early T cell Progenitor Acute Lymphoblastic Leukemia) represents a high-risk subtype of T cell acute lymphocytic leukemia (T-ALL). Therapeutically, ETP-ALL patients frequently relapse after conventional chemotherapy highlighting the need for alternative therapeutic approaches. Using our ZEB2 Tg ETP-ALL mouse model we previously documented the potential utility of the catalytic LSD1 inhibitor (GSK2879552) for treating mouse/human ETP-ALL. However, this approach proved to be inefficient, especially in killing human LOUCY cell ETP-ALL xenografts in vivo. Here we have revealed the novel involvement of ZEB2/LSD1 complexes in repressing the intrinsic apoptosis pathway by inhibiting the expression of several pro-apoptotic proteins such as BIM ( BCL2L11 ) as a major driver for ETP-ALL survival. Treatment with LSD1 i (particularly with the steric inhibitor SP2509) restored the expression of ZEB2/LSD1 pro-apoptotic BIM ( BCL2L11 ) target. In combination with a JAK/STAT pathway inhibitor (JAK i , Ruxolitinib) or with a direct inhibitor of the anti-apoptotic BCL2 protein (BCL2 i , ABT-199) resistance of human and mouse ETP-ALL to LSD1 i was reversed. This new combination approach efficiently inhibited the growth of human and mouse ETP-ALL cells in vivo by enhancing their differentiation and triggering an apoptotic response. These results set the stage for novel combination therapies to be used in clinical trials to treat ETP-ALL patients.
<i>Notes from the Field: </i>Antihistamine Positivity and Involvement in Drug Overdose Deaths — 44 Jurisdictions, United States, 2019–2020
Authors: Amanda T. Dinwiddie, Lauren J. Tanz, Jessica Bitting
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Antihistamines are frequently used to treat allergy symptoms (1).Misuse of antihistamines has been documented primarily in adolescents and young adults (2); however, antihistamine involvement in overdose deaths has not been widely studied.Among the various antihistamine subtypes, the first-generation H1 subtype can cause anticholinergic effects, including strong sedation (3) that might be exacerbated when co-used with other sedative drugs (e.g., opioids).*Diphenhydramine, a common over-the-counter first-generation H1 antihistamine, has been combined with opioids as an adulterant † in illicit drug supply (4) and can be used to reduce opioid-related side effects (e.g., itchy skin because of histamine release from opioid use).To describe unintentional and undetermined intent overdose deaths with antihistamine positivity, involvement, or both, CDC analyzed available 2019-2020 data from the State Unintentional Drug Overdose Reporting System (SUDORS) in 43 states and the District of Columbia.§, ¶ A death was * https://www.elsevier.com/books/a-manual-of-adverse-drug-interactions/griffin/978-0-444-82406-6 † Adulterants are substances mixed with illicit drugs to lengthen the lifespan of the resulting product.Adulterants are pharmacologically active ingredients (e.g., caffeine and phenacetin).§ SUDORS captures data on fatal unintentional and undetermined intent overdoses.For all captured overdose deaths, SUDORS records all drugs detected by postmortem toxicology, even those not ruled by a medical examiner or coroner as causing death.The medical examiner or coroner lists drugs on the death certificate based on any of the following: postmortem toxicology detection, evidence of drug use at the scene, or witness reports of drug use.¶ Among 48 funded jurisdictions, 43 states and District of Columbia (DC) reported data during January
Adverse Childhood Experiences During the COVID-19 Pandemic and Associations with Poor Mental Health and Suicidal Behaviors Among High School Students — Adolescent Behaviors and Experiences Survey, United States, January–June 2021
Authors: Kayla N. Anderson, Elizabeth A. Swedo, Eva Trinh, Colleen M. Ray, Kathleen H. Krause, Jorge V. Verlenden, Heather B. Clayton, Andrés Villaveces, Greta M. Massetti, Phyllis Holditch Niolon
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Social and educational disruptions during the COVID-19 pandemic have exacerbated concerns about adolescents' mental health and suicidal behavior. Data from the 2021 Adolescent Behaviors and Experiences Survey (ABES) indicate that 37.1% of U.S. high school students reported poor mental health during the COVID-19 pandemic, with 19.9% considering and 9.0% attempting suicide in the preceding year (1). Adverse childhood experiences (ACEs)* are associated with poor mental health and suicidal behaviors (2,3), and high prevalence of some ACEs have been documented during the pandemic (4). ACEs are preventable, potentially traumatic events that occur in childhood (ages 0-17 years) such as neglect, experiencing or witnessing violence, or having a family member attempt or die by suicide. Also included are aspects of a child's environment that can undermine their sense of safety, stability, and bonding. Associations between ACEs occurring during the pandemic and mental health or suicidal behaviors among U.S. high school students were examined using ABES data. Experience of one to two ACEs was associated with poorer mental health and increased suicidal behaviors, and these deleterious outcomes increased with additional ACE exposure. After adjusting for demographic characteristics, adolescents who reported four or more ACEs during the pandemic had a prevalence of poor current mental health four times as high as, and a prevalence of past-year suicide attempts 25 times as high as, those without ACEs during the pandemic. Experience of specific ACE types (e.g., emotional abuse) was associated with higher prevalences of poor mental health and suicidal behaviors. Prevention and intervention strategies (5), including early identification and trauma-informed mental health service and support provision, for ACEs and their acute and long-term impacts could help address the U.S. child and adolescent mental health and suicide crisis.†.
Effect of Exercise Training or Complex Mental and Social Activities on Cognitive Function in Adults With Chronic Stroke
Authors: Teresa Liu-Ambrose, Ryan S. Falck, Elizabeth Dao, John R. Best, Jennifer C. Davis, Kim Bennett, Peter A. Hall, Ging-Yuek Robin Hsiung, Laura E. Middleton, Charles H. Goldsmith, Peter Graf, Janice J. Eng
Journal: JAMA Network Open (2022)

Importance A stroke doubles one’s risk for dementia. How to promote cognitive function among persons with chronic stroke is unclear. Objective To evaluate the effect of exercise (EX) or cognitive and social enrichment activities (ENRICH) on cognitive function in adults with chronic stroke. Design, Setting, and Participants This was a 3-group parallel, single-blinded, single-site, proof-of-concept randomized clinical trial at a research center in Vancouver, British Columbia, Canada. Participants included community-dwelling adults with chronic stroke, aged 55 years and older, able to walk 6 meters, and without dementia. The trial included a 6-month intervention and a 6-month follow-up. Randomization occurred from June 6, 2014, to February 26, 2019. Measurement occurred at baseline, 6 months, and 12 months. Data were analyzed from January to November 2021. Interventions Participants were randomly allocated to twice-weekly supervised classes of: (1) EX, a multicomponent exercise program; (2) ENRICH, a program of cognitive and social enrichment activities; or (3) balance and tone (BAT), a control group that included stretches and light-intensity exercises. Main Outcomes and Measures The primary outcome was the Alzheimer Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus), which included the 13-item ADAS-Cog, Trail Making Test Parts A and B, Digit Span Forward and Backward, Animal Fluency, and Vegetable Fluency. Results One-hundred and twenty participants, with a mean (range) of 1.2 (1-4) strokes, a mean (SD) of 66.5 (53.8) months since the most recent stroke, mean (SD) baseline age of 70 (8) years, mean (SD) baseline ADAS-Cog-Plus of 0.22 (0.81), and 74 (62%) male participants, were randomized to EX (34 participants), ENRICH (34 participants), or BAT (52 participants). Seventeen withdrew during the 6-month intervention and another 7 during the 6-month follow-up. Including all 120 participants, at the end of the 6-month intervention, EX significantly improved ADAS-Cog-Plus performance compared with BAT (estimated mean difference: −0.24; 95% CI, −0.43 to −0.04; P = .02). This difference did not persist at the 6-month follow-up (estimated mean difference: −0.08; 95% CI, −0.29 to 0.12; P = .43). For the 13-item ADAS-Cog, the EX group improved by 5.65 points over the 6-month intervention (95% CI, 2.74 to 8.57 points; P &amp;amp;lt; .001), exceeding the minimally clinical difference of 3.0 points. Conclusions and Relevance These findings suggest that exercise can induce clinically important improvements in cognitive function in adults with chronic stroke. Future studies need to replicate current findings and to understand training parameters, moderators, and mediators to maximize benefits. Trial Registration ClinicalTrials.gov identifier: NCT01916486
Comparison of Quality Measures From US Hospitals With Physician vs Nonphysician Chief Executive Officers
Authors: Helen See, Lacey Shreve, Sarah Hartzell, Sarah Daniel, Anthony D. Slonim
Journal: JAMA Network Open (2022)

Importance Patient experience and patient safety are 2 major domains of health care quality; however empirical data on the association of physician vs nonphysician chief executive officers (CEOs) with public and private quality measures are rare but critical to evaluate as hospitals increasingly seek out physician CEOs. Objectives To evaluate whether there is an association of CEO background with hospital quality and to investigate differences in hospital characteristics between hospitals with a physician CEO vs those with a nonphysician CEO. Design, Setting, and Participants This cross-sectional study used 2019 data from 3 sources (ie, the American Hospital Association [AHA] Annual Survey, the Hospital Consumer Assessment of Healthcare Providers and Systems [HCAHPS], and the Leapfrog Hospital Safety Grades) to identify statistical differences in hospital characteristics and outcomes. Data were analyzed from April to December 2021 . Main Outcomes and Measures Multivariable ordinal logistic regression was used to examine the association of physician CEOs with hospital quality assessment outcomes while controlling for other confounding factors. Characteristics from the AHA Annual Survey database were assessed as potential confounders, including hospital control, bed size, region, teaching status, and patient volume. Results The AHA database contained 6162 hospitals; 1759 (29%) had HCAHPS ratings, 1824 (30%) had Leapfrog grades, and 383 (6%) had physician CEOs. A positive Spearman correlation coefficient was found between physician CEOs and HCAHPS patient willingness to recommend the hospital (ρ = 0.0756; P = .002), but the association between CEO medical background and Leapfrog safety grades or HCAHPS ratings did not reach a level of significance in the multivariable ordinal logistic regression models. Conclusions and Relevance In this study, a positive correlation was found between physician CEOs and HCAHPS patient willingness to recommend the hospital, but the multivariable analysis did not find an association between hospital physician CEOs and the examined quality and safety outcomes.
Development of a Prediction Model for the Management of Noncommunicable Diseases Among Older Syrian Refugees Amidst the COVID-19 Pandemic in Lebanon
Authors: Stephen J. McCall, Tanya El Khoury, Noura Salibi, Berthe Abi Zeid, Maria El Haddad, Marwan F. Alawieh, Sawsan Abdulrahim, Monique Chaaya, Hala Ghattas, Abla M. Sibai
Journal: JAMA Network Open (2022)

Importance Older Syrian refugees have a high burden of noncommunicable diseases (NCDs) and economic vulnerability. Objectives To develop and internally validate a predictive model to estimate inability to manage NCDs in older Syrian refugees, and to describe barriers to NCD medication adherence. Design, Setting, and Participants This nested prognostic cross-sectional study was conducted through telephone surveys between September 2020 and January 2021. All households in Lebanon with Syrian refugees aged 50 years or older and who received humanitarian assistance from a nongovernmental organization were invited to participate. Refugees who self-reported having chronic respiratory disease (CRD), diabetes, history of cardiovascular disease (CVD), or hypertension were included in the analysis. Data were analyzed from November 2021 to March 2022. Main Outcomes and Measures The main outcome was self-reported inability to manage any NCD (including CRD, CVD, diabetes, or hypertension). Predictors of inability to manage any NCD were assessed using logistic regression models. The model was internally validated using bootstrapping techniques, which gave an estimate of optimism. The optimism-adjusted discrimination is presented using the C statistic, and calibration of the model is presented using calibration slope ( C slope). Results Of 3322 older Syrian refugees, 1893 individuals (median [IQR] age, 59 [54-65] years; 1089 [57.5%] women) reported having at least 1 NCD, among whom 351 (10.6% overall; 18.6% of those with ≥1 NCD) had CRD, 781 (23.7% overall; 41.4% of those with ≥1 NCD) had diabetes, 794 (24.1% overall; 42.2% of those with ≥1 NCD) had history of CVD, and 1388 (42.3% overall; 73.6% of those with ≥1 NCD) had hypertension. Among individuals with NCDs, 387 participants (20.4%) were unable to manage at least 1 of their NCDs. Predictors for inability to manage NCDs were age, nonreceipt of cash assistance, household water insecurity, household food insecurity, and having multiple chronic diseases, with an adjusted C statistic of 0.650 (95% CI, 0.620-0.676) and C slope of 0.871 (95% CI, 0.729-1.023). The prevalence of nonadherence to medication was 9.2%, and the main reasons for nonadherence were unaffordability of medication (40.8%; 95% CI, 33.4%-48.5%) and the belief that they no longer required the medication after feeling better (22.4%; 95% CI, 16.4%-29.3%). Conclusions and Relevance In this cross-sectional study, the predictors of inability to manage NCDs among older Syrian refugees in Lebanon were mainly related to financial barriers. Context-appropriate assistance is required to overcome financial barriers and enable equitable access to medication and health care.